1. Field of the Invention
This invention describes methods and compositions for ameliorating the effects of rosacea, especially in combination with conventional therapy.
2. The State of the Art
Rosacea is a common facial dermatitis that currently affects an estimated 13 million Americans. It is a chronic and progressive cutaneous vascular disorder, primarily involving the malar and nasal areas of the face. Rosacea is characterized by flushing, erythema, papules, pustules, telanglectasia, facial edema, ocular lesions, and, in its most advanced and severe form, hyperplasia of tissue and sebaceous glands leading to rhinophyma. Rhinophyma, a florid overgrowth of the tip of the nose with hypervascularity and modularity, is an unusual progression of rosacea of unknown cause. Ocular lesions are common, including mild conjunctivitis, burning, and grittiness. Blepharitis, the most common ocular manifestation, is a nonulcerative condition of the lid margins.
Rosacea most commonly occurs between the ages of 30 to 60, and may be seen in women experiencing hormonal changes associated with menopause. Women are more frequently affected than men; the most severe cases, however, are seen in men. Fair complexioned individuals of Northern European descent are most likely to be at risk for rosacea; most appear to be pre-disposed to flushing and blushing.
Alcohol, stress, spicy foods, and extremes of temperature have all been implicated, but none have been found to actually cause rosacea. One of the most famous rosacea sufferers was W. C. Fields; his on-screen association with alcohol likely fostered the unsubstantiated association between alcohol and rosacea. Although papules and pustules are associated with rosacea, and hence its misnomer as “acne rosacea”, the occurrence of P. acnes is generally not associated with the condition.
The cause of rosacea is poorly understood, numerous theories have been offered. Hypotheses have included gastrointestinal, psychological, infectious, climatic, and immunological causes, although scientific evidence has not substantiated any of these as primary. Controlled studies have not demonstrated consistent preponderance of gastrointestinal symptoms in rosacea patients. Similarly, neither a distinct psychological abnormality nor one pharmacological mechanism has been isolated in rosacea patients. Perhaps the most commonly touted of the etiologic theories is based on the presence of Demodex folliculorum mites in patients with rosacea; the organism feeds on sebum, and in some cases treatment of demodex infestation has noted improvement in the rosacea; however, in a review of 79 biopsies in 1969, demodex folliculorum was noted in only 19% of the specimens. A bacterial cause for the disease has been hypothesized, but no consistent findings of one bacteria have been demonstrated. Climate, specifically exposure to extremes of sun and cold, may have an effect on the course of the disease, but the role of climate in what appears to be a connective tissue disorder is not clear. An autoimmune process has been suggested, and tissue fixed immunoglobulins have been reported in patients with chronic inflammation of rosacea, but no other evidence has been found. Other experimental evidence has suggested this disease may represent a type of hypersensitivity reaction. No single hypothesis appears to adequately explain both the vascular changes and the inflammatory reaction seen in rosacea, leaving the pathogenesis unclear. More recently, certain investigators have suggested a connection between rosacea and H. pylori, a bacteria shown to cause certain gastrointestinal ulcers, because symptoms seem to have abated in some ulcer patients also suffering rosacea. Nevertheless, the connection between H. pylori and rosacea has been questioned. H. Herr, J Korean Med Sci 2000 October; 15(5):551–4; R. Boni, Schweiz Med Wochenschr 2000 Sep. 16;130(37):1305–8.
Histopathologic findings in rosacea dermatitis include vascular dilatation of the small vessels with perivascular infiltration of histiocytes, lymphocytes, and plasma cells. Dermal changes include loss of integrity of the superficial dermal connective tissue with edema, disruption of collagen fibers, and frequently severe elastosis. Follicular localization is infrequent and, when seen, is usually manifest clinically as pustules. However, there is no primary follicular abnormality. Rhinophyma is characterized histologically by an increase in sebaceous glands and connective tissue, follicular and vascular dilatation, edema, and a scattered infiltrate of perivascular lymphocytes and histiocytes. Immunoglobulin and compliment deposition at the dermal epidermal junction have been reported in conjunctival and skin biopsies from rosacea patients. Ocular pathologic findings include conjunctival and corneal infiltration with chronic inflammatory cells, including lymphocytes, epithelioid cells, plasma cells, and giant cells.
For the dermatological disease, the outcome of a successful management regimen is usually control rather than eradication of the disease. Advising the patient to avoid those stimuli that tend to exacerbate the disease—exposure to extremes of heat and cold, excessive sunlight, ingestion of hot liquids, alcohol, and spicy foods—may help. Although its mechanism of action is not clearly understood, the mainstay of treatment is the use of oral tetracycline, especially for the papular or pustular lesions. The dosage utilized is generally 250 mg every 6 hours for the first 3 to 4 weeks, followed by tapering based on clinical response. Doxycycline and minocycline (50–100 mg every 12 hours) are also effective and have the advantage of less frequent dosage and less concern over problems with gastrointestinal absorption. Patients who are intolerant to the tetracyclines may benefit from the use of erythromycin. Oral isotretinoin, in doses similar to those used for acne vulgaris, has also been effective for the inflammatory lesions, erythema, and rhinophyma. There is, however, no beneficial effect on the telangiectasias and isotretinoin may cause blepharitis and conjunctivitis. Other oral agents that have been used include ampicillin and metronidazole. Clonidine may also be of some value in reducing facial flushing. Topical therapy for rosacea is generally less successful than systemic treatment, although often tried first. Metronidazole (2-methyl-5-nitroimidazole-1-ethanol) may be effective topically; it is available commercially as a 0.75% gel and, when applied twice daily, substantially reduces inflammatory lesions; it is classified as an antiprotozoal. Although topical corticosteroid s may effectively improve signs and symptoms, long-term therapy is not advisable since it may cause atrophy, chronic vasodilation, and telangiectasia formation. The treatment of chronic skin changes may require surgical intervention. Telangiectasias may be treated by electrocautery or using the tunable dye laser. Severe rhinophyma is treated by paring with a scalpel, excision with skin grafting, dermabrasion, bipolar electrocautery, or by means of the argon or carbon dioxide laser.
The typical course of treatment is to start with metronidazole, and if that is not as effective as desired to ameliorate the symptoms, or the condition worsens, then therapy is switched to a stronger antimicrobial, such as tetracycline or minocycline. This standard course of therapy persists under the pretense that the antimicrobial is reducing inflammation, because inflammation appears to be reduced, even though it is logically the antimicrobial effects that cause the reduction in inflammation (and because these types of compounds are not known to have antiinflammatory properties).
In 1990, Akamatsu et al. (“The inhibition of free radical generation by human neutrophils through the synergistic effects of metronidazole with palmitoleic acid: a possible mechanism of action of metronidazole in rosacea and acne,” Arch Dermatol Res 1990;282(7):449–54) described the synergistic effects of metronidazole and palmitoleic acid on the anaerobic growth of P. acnes as well as on human neutrophil functions, including the generation of reactive oxygen species (ROS). Both metronidazole and palmitoleic acid, when used alone, only slightly inhibited the growth of P. acnes, and no significant decrease in human neutrophil functions, including the generation of ROS, was observed; but metronidazole used in the presence of palmitoleic acid (naturally present in human skin) markedly inhibited the anaerobic growth of P. acnes and decreased ROS generation by neutrophils. They conclude that by inhibiting oxidative tissue injury under in vivo conditions, treatment with metronidazole results in remarkable improvement of rosacea and acne.
U.S. Pat. No. 6,228,887 to Kligman discloses treating such skin disorders as photodamage, hyperpigmentation, rosacea, and scarring topically with high strength retinoids at a concentration effective to cause desquamation. Retinoids activate the the epidermal growth factor receptor, causing hyperproliferation of skin cells, which results in the desquamation sought by this patent. The clinical examples given in this patent only involve treating photodamaged skin.